Pancreatic Cancer May Kill More Slowly than Believed

Action Points

Explain to interested patients that based upon mutation analysis, pancreatic cancer may actually begin to develop two decades before a patient succumbs.

Note that, according to another study, pancreatic cancer is genetically highly variable with one-sixth of the mutations having a distinctive pattern.

Pancreatic cancer -- long thought to be an extraordinarily swift killer -- may actually begin to develop two decades before a patient succumbs, researchers reported.

The finding opens the possibility that improved screening might reduce mortality from the disease, which usually kills within a few years of diagnosis, according to Christine Iacobuzio-Donahue, MD, PhD, of Johns Hopkins University, and colleagues.

But the challenge is to find ways of detecting pancreatic cancer before it begins to spread, Iacobuzio-Donahue and colleagues argued in the Oct. 28 issue of Nature.

"There is potentially a very broad window for screening," Iacobuzio-Donahue said in a statement. But currently "pretty much everybody is diagnosed after that window has closed."

She and her colleagues did a detailed genetic study of pancreatic cancers from seven patients who died of the disease.

They first sequenced the so-called "index" lesion -- one of the metastatic tumors -- from each of the patients, finding an average of 61 mutations per lesion. Then they compared those mutations with those found in other distant metastases and also in the primary tumor in the pancreas.

On average, 64% of the mutations were present in all samples, and were regarded as having arisen in the primary tumor; 36% were found in one or the other metastatic tumor, but not in the primary tumor.

Analysis of the primary tumors from each patient showed that they were composed of subclones -- large clumps of about 100 million cells with similar genetics. Some of the subclones corresponded genetically to one or another of the metastatic tumors, but others did not, the researchers reported.

They used the data to "infer the timing of the development of the various stages of pancreatic tumor progression."

Specifically, they found:

It takes an average of 11.7 years from the first step in tumorigenesis until a cell arises that has all the mutations found in the parental tumor.

After another 6.8 years, on average, a cell arises that has all the mutations in the index lesion.

2.7 years after that, on average, the patient dies.

In a companion paper in the journal, researchers led by Andrew Futreal, PhD, of the Wellcome Trust Sanger Institute in Hinxton, England, showed that pancreatic cancer is genetically highly variable, with patterns of "ongoing, parallel, and even convergent evolution among different metastases."

The research team (which included Iacobuzio-Donahue) found that about a sixth of all the mutations they found had a distinctive pattern dubbed "fold-back inversions," in which a genomic region is duplicated, but the two copies have opposite orientations.

Many other types of mutations were also found, generating what the researchers called "a distinctive pattern of genomic instability" for pancreatic cancer.

But more than half of the mutations occurred in both the primary and metastatic lesions, Futreal and colleagues argued, suggesting that the ability to identify and understand the variants "provides a route to the discovery of drug targets."

Taken together, the two studies are "a bellwether," according to Georg Luebeck, PhD, of the Fred Hutchinson Cancer Research Center in Seattle.

They are "among the first to explore the biological and clinical implications of sequence data for individual tumors," Luebeck argued in an accompanying News&Views article. As sequencing technology advances, he wrote, more details of the evolution of cancer will probably be found.

Such information, he concluded, has the potential to "lead to new approaches to early cancer detection, better prognosis and, ultimately, prevention."

The metastasis study had support from the NIH, the Bill and Melinda Gates Foundation, the Uehara Memorial Foundation, the AACR-Barletta Foundation, the John Templeton Foundation, the Sol Goldman Pancreatic Cancer Research Center, the Michael Rolfe Pancreatic Cancer Foundation, the George Rubis Endowment for Pancreatic Cancer Research, the Joseph C. Monastra Foundation for Pancreatic Cancer Research, the Alfredo Scatena Memorial Fund, the Virginia and D.K. Ludwig Fund for Cancer Research, The Joint Program in Mathematical Biology, and J. Epstein.

The genomic instability study had support from the Wellcome Trust, the Uehara Memorial Foundation, the Skip Viragh Foundation, the Michael Rolphe Foundation Pancreatic Cancer Foundation, the NIH, and the International Human Frontier Science Program Organization.

Authors of both papers said they had no competing financial interests.

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